Excessive fear and anxiety are the trademarks of a number of psychiatric disorders, where people with fear-related disorders are thought to over-learn a fear association and/or exhibit an inability to extinguish that fear association. Fear is modeled in the laboratory via a fear acquisition and fear extinction learning paradigm. Although the neural basis of associative fear acquisition is fairly well understood, the mechanism of extinction learning is less clear. Understanding the neural correlates of extinction learning is imperative to enhancing these extinction processes, thus aiding in the development of therapies for the treatment of PTSD and other fear-related disorders. Studies of cannabinoid receptor (Cb1) knockout mice suggest that the retrograde transmitters known as the endocannabinoids are critical for extinction of conditioned fear1. Although these mice exhibit normal fear acquisition, they are severely impaired in the learned inhibition of fear. In a separate study in or laboratory, the neuropeptide cholecystokinin (CCK) also seems to be involved in extinction learning, as animals treated with the CCK-B receptor agonist, pentagastrin, show higher levels of fear 48 hours after extinction learning, off drug, in a fear potentiated startle behavior assay. Additionally, CCK appears to be an anxiogenic neuropeptide, as administration of exogenous CCK in rodents induces anxiety-like behaviors3. Moreover, CCK-B receptor gene variation may also contribute to the neurobiology of panic disorder4. Interestingly, Cb1 is enriched on cholecystokinin (CCK)-containing interneurons within the basolateral amygdala (BLA), the site of fear acquisition and proposed area of extinction learning. Co-localization of Cb1 and CCK, as well as pharmacology studies, suggest that interplay between Cb1 and CCK systems may be critical to extinction learning5. This proposal will utilize pharmacology, transgenic mice, lentivirus-mediated manipulation of site-specific gene expression, and behavioral assays to explore a potential novel pathway involved in the extinction of aversive memories. PUBLIC HEALTH RELEVANCE: Understanding the molecular and cellular mechanisms mediating fear regulation is of critical importance for the treatment of fear dysregulation disorders, such as Posttraumatic Stress Disorder (PTSD). Through a combination of anatomical, behavioral, molecular, and genetic techniques, these experiments have the potential to delineate the mechanisms by which a cannabinoid/cholecystokinin (Cb1/CCK) interaction is involved in the modulation of fear memories in mammals. Understanding a Cb1/CCK interaction in the mediation of fear may provide a translationally novel and relevant approach toward better comprehension and treatment of fear-related disorders.